A Tale of Two Huxleys

Andrew Huxley is one of the founders of both modern electrophysiology and  computational neuroscience, and is consequently a personal hero of mine. His recent (May 30, 2012) death inspired me to learn more about his life.

Andrew Huxley (1917-2012)

Andrew Huxley along with Alan Hodgkin discovered the mechanisms which governed the action potential in nerve cells. They inserted micro-electrodes into the squid giant axon and recorded the sodium and potassium currents which generated and propagated the action potential. They shared the Nobel prize for physiology and medicine (with John Eccles) in 1963.

(squid giant axon)

Andrew Huxley is a hero of neuroscience because he (along with Alan Hodgkin) was not only able to develop the equipment and techniques necessary for the complex electrophysiological recordings of the squid axon, but he was also able to understand and mathematically interpret the results of their experiments. Hodgkin and Huxley's mathematical interpretation of their experimental results is basically the beginning of modern computational neuroscience. Their equations describing the flow of ions based on voltage and on concentration are still used in computational models of neurons today. Their famous series of papers (1952) in the Journal of Physiology culminates in their mathematical model of the action potential.

Time constants and steady state curves for activation and inactivation of sodium (Na) and potassium (K) channels (source)

This paper is fascinating to read because of the meticulous thought process that can be traced through it, and because of how much was not known about neurons at the time. The simple composition of the cell membrane was not clear and the fact that sodium and potassium ions actually flow in and out of channels formed by proteins was unknown.

"The next question to consider is how changes in the distribution of a charged particle might affect the ease with which sodium ions cross the membrane. Here we can do little more than reject a suggestion which formed the original basis of our experiments (Hodgkin, Huxley & Katz, 1949). According to this view, sodium ions do not cross the membrane in ionic form, but in combination with a lipoid soluble carrier which bears a large negative charge and which can combine with one sodium ion but no more. Since both combined and uncombined carrier molecules bear a negative charge they are attracted to the outside of the membrane in the resting state. Depolarization allows the carrier molecules to move, so that the sodium current increases and membrane potential is reduced. The steady state relation between sodium current and voltage could be calculated for this system and was found to agree reasonable with the observed curve at 0.2msec after the onset of a sudden depolarization. This was encouraging, but the analogy breaks down if it is pursued further. In the model the first effect of depolarization is a movement of negatively charged molecules from the outside to the inside of the membrane. This gives an initial outward current, and an inward current does not occur until combined carriers lose sodium to the internal solution and return to the outside of the membrane. In our original treatment the initial outward current was reduced to vanishingly small proportions by assuming a low density of carriers and a high rate of movement and combination. Since we now know that sodium current takes an appreciable time to reach its maximum, it is necessary to suppose that there are more carriers and that they react or move more slowly. This means that any inward current should be preceded by a large outward current. Our experiments show no sign of a component large enough to be consistent with the model. This invalidates the detailed mechanism assumed for the permeability change but it does not exclude the more general possibility that sodium ions cross the membrane in combination with the lipoid soluble carrier. " (Hodgkin &Huxley 1952) (emphasis mine)

They describe the ions being bound on one side of the membrane, carried through and released on the other side. If you did not have any idea about membrane channels, this would make sense. What is so beautiful about this is that their experiments and model constrain the vague theory.  However the ions get across the membrane, it must be this fast, this strong, and this dependent on temperature.
They continue:

                "A different form of hypothesis is to suppose that sodium movement depends on the distribution of charged particles which do not act as carriers in the usual sense, but which allow sodium to pass through the membrane when they occupy particular sites on the membrane. On this view the rate of movement of the activating particles determines the rate at which the sodium conductance approaches its maximum but has little effect on the magnitude of conductance. It is therefore reasonable to find that temperature has a large effect on the rate of rise of sodium conductance but a relatively small effect on its maximum value. In terms of this hypothesis one might explain the transient nature of the rise in sodium conductance by supposing that the activating particles undergo a chemical change after moving from the position which they occupy when the membrane potential is high. An alternative is to attribute the decline of sodium conductance to the relatively slow movement of another particle which blocks the flow of sodium ions when it reaches a certain position in the membrane." (Hodgkin &Huxley 1952) (emphasis mine)

Without any structural or molecular analysis of the membrane, Hodgkin and Huxley speculate that there might be sodium channels. They also discuss whether potassium has an entirely separate mechanism of membrane-transport, or whether it is the same one as sodium, but switched in affinity and timecourse in response to membrane depolarization.  Rather than quoting the entire paper here, I urge you to read it as an example of a truly beautiful train of scientific thought.

Aldous Huxley (1894-1963)

Speaking of truly beautiful trains of thought, a different Huxley, half brother to Andrew and 23 years his senior, was a world famous novelist. Aldous Huxley is known best for writing Brave New World, a dystopian novel about a 'perfect' future in which everyone has a place and likes it.

"Till at last the child's mind is these suggestions, and the sum of the suggestions is the child's mind. And not the child's mind only. The adult's mind too-all his life long. The mind that judges and desire and decides-made up of these suggestions. But all these suggestions are our suggestions... Suggestions from the State."
- Aldous Huxley, Brave New World, Ch. 2

Aldous Huxley was on track to become a scientist or doctor, but was struck by an illness which rendered him functionally blind for 3 years, preventing him from maintaining this course of study.

I am not sure which delights me more, that Aldous Huxley is a novelist with a scientist brother, or that Andrew Huxley is a scientist with a novelist brother.

© TheCellularScale

HODGKIN AL, & HUXLEY AF (1952). A quantitative description of membrane current and its application to conduction and excitation in nerve. The Journal of physiology, 117 (4), 500-44 PMID: 12991237